This invention describes a new, improved process for synthesis of 9-cyclohexyl-2-alkoxy-9H-adenine derivatives and in particular to preparation of the non-adrenergic bronchodilating agent 9-cyclohexyl-2-n-propoxy-9H-adenine.
Regarding previous synthesis of such compounds, Naito, et al., U.S. Pat. No. 4,172,829 disclose methods for converting 2,6-dichloropurine (1) to 9-cyclohexyl-2-alkoxy-9H-adenine (7) as depicted in the reaction scheme below wherein R is C.sub.1 -C.sub.6 alkyl, M is Na, K, Tl, Ag, or HgCl, X is Cl, Br or I, and Alk is sodium or potassium. ##STR1##
E. C. Taylor, et al., J. Org. Chem., 36(21), 3211 (1971) describe preparation of 2-, 8-, and 9-substituted adenines (6) according to the following outline. ##STR2## Reductive cleavage of compound (4) (step d) is thought to involve initial hydrogenolysis of the furazan ring to give an intermediate 4-acylamino-5,6-diaminopyrimidine (5) which then spontaneously cyclizes to adenine (6).
G. D. Hartman, et al., J. Org. Chem. 43(5), 960 (1978) describe synthesis of a (2-chloro-6-fluorobenzyl)adenine (6) utilizing a formylated 7-amino[1,2,5]thiadiazolo[3,4-d]pyrimidine intermediate (4) as set forth below. ##STR3##